Objectives of the proposed work are evaluation of biochemical effects of known and new anticancer agents on colon tumors and on normal tissues in mice. Effects of inhibitors of pyrimidine biosynthesis on metabolism in tumors and normal tissues and effects of such inhibitors on metabolism and action of pyrimidine analogs will be examined. Combinations of inhibitors of pyrimidine biosynthesis, such as N-(phosphonacetyl)-L-aspartate (PALA) and pyrazofurin, with fluorinated pyrimidines and with cytidine analogs are of particular interest. Metabolism of purine analogs, such as 6-thiopurines and 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-AraA), their metabolic effects, and effects of nitrosoureas in combination with these analogs in murine colon tumors constitute another area of proposed research. We propose to examine levels of selected enzymes of purine and pyrimidine metabolism in murine colon tumors and to extend these studies to human colon tumors and normal tissues. Alkylating agents (MeCCNU, cyclophosphamide) that are known to produce therapeutic responses in murine and human colon carcinoma will be studied for their effects in vivo on DNA of murine colon carcinoma and normal tissues. Proposed studies will include extent of alkylation, chain scission, cross-linking and repair.